Method and Apparatus for Cardiac Tissue Monitoring and Catheter-Based Perfusion for Mitigating Acute Reoxygenation Injury

ABSTRACT

A system and methods are described for improving the management of ischemic cardiac tissue during acute coronary syndromes or other ischemic conditions. A method and apparatus is described that allows mitigation of oxygen-related injury by precisely modulating the level of oxygen re-exposure during reoxygenation by a controlled feedback loop based on parameters of the tissue measured by a real-time tissue sensor or probe.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a continuation application of and claimspriority to U.S. application Ser. No. 14/524,254, titled, “Method andApparatus for Cardiac Tissue Monitoring and Catheter-Based Perfusion forMitigating Acute Reoxygenation Injury”, and filed on Oct. 27, 2014,which is a divisional application of and claims priority to U.S.application Ser. No. 12/582,515, titled, “Method and Apparatus forCardiac Tissue Monitoring and Catheter-Based Perfusion for MitigatingAcute Reoxygenation Injury”, filed on Oct. 20, 2009. The entire contentsof the foregoing priority applications are hereby incorporated herein byreference.

FIELD OF THE INVENTION

The invention relates to the clinical arena of interventional cardiologyand, in particular, the field of percutaneous coronary interventions andtreatments for acute coronary syndrome (including acute myocardialinfarction and/or unstable angina). A method and apparatus is describedthat provides the ability to mitigate oxygen-related injury bymodulating the level of oxygen re-exposure during reperfusion using afeedback loop that provides information regarding the condition of thetissue being addressed.

BACKGROUND

Considerable effort and resources have been devoted to reducing theburden of cardiovascular disease and mortality rates after acutemyocardial infarction have decreased over the past 30 years. However,coronary artery disease remains the leading cause of morbidity andmortality in the developed world. An estimated 79.4 million Americanadults (1 in 3) have one or more types of cardiovascular disease. Ofthese, an estimated 1.4 million Americans per year will have amyocardial infarction and another 500,000 present with other forms ofacute coronary events that lead to cardiac ischemia. In 2007, anestimated 1.68 million patients were discharged in the US suffering fromacute coronary syndrome. In 2004, an estimated 6,363,000 in-patientcardiovascular operations and procedures were performed in the UnitedStates. These included an estimated 1,285,000 in-patient angioplastyprocedures, 427,000 in-patient bypass procedures and 1,471,000in-patient diagnostic cardiac catheterizations (see Rosamond et al.(2007) Heart Disease and Stroke Statistics—2007 Update. Circulation.115:e69-e171).

For patients who suffer from any form of acute coronary syndrome, theheart muscle is deprived of adequate levels of oxygen until appropriatetreatment can be initiated. The deprivation can occur for a variableperiod of time and along a spectrum of severity. In many cases,irreversible damage to the heart can result in infarction, with celldeath occurring in one of more areas of the left ventricular or rightventricular myocardium or within the conduction system of the heart. Inaddition to the effects of this lack of available oxygen oncardiomyocytes and conduction tissue, it has become increasinglyrecognized that the endothelial cells lining the blood vessels can alsobe damaged or can become impaired in their ability to function.Furthermore, the recognition of the importance of the endothelial liningof the vasculature has allowed a broader understanding of the resultantmicrovascular dysfunction that can follow even successful reperfusion ofthe epicardial or larger arterial or arteriolar supply. This alsohighlights the need for more appropriate means by which to mitigatepost-ischemic patterns of injury.

In human beings with acute coronary insufficiency, ischemia is usuallynot limited merely to the area supplied by an artery affected by acuteocclusion.

Modern treatment of acute myocardial infarction or myocardial ischemiaoften comprises performing percutaneous intervention on the vessels tofacilitate increased blood flow. Coronary interventions typicallyinclude procedures that generally require advancing a guiding wirethrough an artery into a region of obstruction; advancing a catheterincluding a dilation device such as a balloon over that wire through theoffending lesion; and then inflating the device, i.e. the angioplastyballoon, to eliminate the lesion. After deflation, the artery is thenopen to existing blood flow. Other methods of eliminating lesionsinclude angioplasty with stent deployment, directional atherectomy withor without distal protection, laser therapy, intracoronary declottingand ultrasound devices. Such procedures can all be broadly considered tobe part of the clinical arena of percutaneous coronary intervention(PCI).

In the setting of acute coronary events, current ACC/AHA guidelinesregarding acute percutaneous coronary interventions exist to determinethe timing, among other clinically relevant parameters, of PCI and tosteer the operator to (or away from) the heart catheterization lab.These guidelines are based upon the “clinical condition” of the patientand focus largely upon the appearance of an EKG, time from onset ofsymptoms, the clinical appearance of the patient, including hemodynamicparameters, and, sometimes, other “thrombolysis in myocardialinfarction” trial (TIMI) risk factors defined a decade or longer ago.Although guided by well-defined and well-studied clinical indicators,the clinical assessment of a patient with an acute evolving coronarysyndrome is known to be imprecise. Often times, a patient may be unclearon when the syndrome began, may have mistaken his or her symptoms for adifferent condition and may have even attributed them incorrectly tosomething unrelated to the heart. An assessment of the time from theonset of symptoms and the amount of time that may elapse between thepatients' arrival to emergency care and the inflation of an angioplastyballoon can often only be estimated and is highly variable. This lack ofprecision can predispose to significant, additive cardiac injury thatrelates to both the inciting syndrome and the approach taken by theclinician. One unintended consequence of the comparatively successfuland widespread catheter-based treatment of such acute coronaryconditions has been an increase in chronic heart failure related toischemic cardiac injury. This syndrome is otherwise known as ischemiccardiomyopathy and represents the most common form of congestive heartfailure in the U.S. and the developed world in patients with associatedleft ventricular systolic impairment. Heart failure specialists have,for years; pointed out that in the modern era we have exchanged areduction in death from acute myocardial infarction for an epidemic ofchronic congestive heart failure.

Without modification, the goal of acute PCI therapy during acutecoronary events is to reestablish normal blood flow in the narrowed oroccluded artery. However, it has become clear that immediate reperfusionwith arterial blood in certain circumstances causes extensive, andpotentially lethal, reperfusion injury. In fact, because of therealization of the potential for such injury, many patients for whomthis invention will benefit would not otherwise be offered immediatereperfusion therapy. Such patients are those in whom the coronarysyndrome is known to have been progressing for a considerable period oftime. Time to reperfusion, as a result, has become a benchmark standardin the treatment of many such patients. If too much time has elapsed,many patients are treated medically, allowed to “cool-off” and, if theysurvive, are approached much later after significant damage to the“tissue at risk” has occurred.

Reoxygenation injury can occur after reestablishing blood flow(perfusion) in a previously ischemic tissue. The severity of theischemic conditions sets the stage for significant oxygen-related andother damage depending upon certain conditions that exist once flow isreestablished or ischemia is eliminated. Even a brief period of abruptoxygen re-exposure after ischemia can initiate damaging oxidative stressand result in numerous inflammatory responses. Key calcium ionfluctuations triggered by the presence of molecular oxygen that lead tovarious degrees of contracture can also occur. Countless other molecularmechanisms and pathways, are also involved and may lead to bothimmediate and delayed cellular injury and swelling within the cytosolic,mitochondrial and sarcoplasmic reticular membranes and can ultimatelylead to incremental or catastrophic cellular damage or death. Ourunderstanding in this regard points to thousands of years of evolvingmechanisms for tolerating ischemic injury that can be harmful uponexposure to abrupt reperfusion initiating by modern treatmentmodalities.

Although, several methods have been proposed to combat the effects ofthis pattern of oxygen and reperfusion-related injury, these have beeneither misguided or ineffective. For examples, proposed methods includesthose aimed at supplying superoxygenated fluids to previously ischemictissue (see for eg. U.S. Patent Publication No. 2005/0042132) to “force”oxygen into the damaged areas, or methods of reducing the temperature ofthe reperfusion fluids to reduce metabolic load of the cells. None ofthese methods has offered a realizable approach to actually preventingor reducing reperfusion-related injury in the population of patientsmost seriously affected by acute ischemia.

Certain groups have proposed feedback systems to guide reperfusiontherapy. For example, U.S. Pat. No. 5,533,957 to Aldea provides aretroperfusion catheter that can be adjusted based on pressure feedback.Similarly, U.S. Pat. No. 6,481,439 to Salient Interventional Systems,Inc. and related cases provide catheters that allow feedback control ofa reperfusate based on pressure of the downstream fluids. U.S. Pat. No.7,218,964 and related cases to Medtronic provide a closed loop systemfor providing electrical stimulation to the spinal cord to regulate theautonomic nervous sytem. U.S. Patent Publication No. 2007/0169779 toFreeman provides an apparatus for resuscitating a patient using aventilator adjustable based on certain tissue parameters. U.S. PatentPublication No. 2006/0142826 to Willard provides a system for targeteddelivery of supercooled fluids that can be regulated based ontemperature feedback. U.S. Patent Publication No. 2006/0100639 to Levinprovides certain methods in which reperfusion therapy is delivered tothe patient based on pressure feedback. However, these feedback systemslimited to pressure or temperature concerns of the perfusate.

There remains a need for improved methods and apparatus to reducereperfusion injury. There specifically remains a need for a method andapparatus that provides improved control over tissue conditions that canbe linked to catheter-based therapies that do not require surgery or asan adjunct to myocardial protection strategies used during open-heartsurgery and acute coronary bypass surgery.

It is therefore an object of the present invention to provide improvedmethods and apparatuses for controlled reoxygenation of ischemic tissue.It is another object of the invention to reduce reperfusion injury andprovide improved patient outcome across a broader spectrum of thepopulation being treated for acute coronary syndrome.

SUMMARY OF THE INVENTION

The present invention is based on a recognition that reoxygenation ofpreviously ischemic tissues should be carefully modulated in response tolocal tissue conditions and guided by the dynamic changes that occurupon manipulation of the circulatory system. It is not generallyappreciated that such manipulation (either mechanical or pharmacologic)can directly impact the local tissue condition by altering both supplyof, and demand for, oxygen at the level of the individual cells and thetissue as a whole. The methods and apparatus described herein directlyaddress the need to be responsive to the actual conditions within thelocal environment of the ischemic tissue by using sensors or probes tomeasure the condition of the tissue affected by the ischemic insult andthen control reperfusion in response to the changing conditions of thatischemic tissue.

Accordingly, in one embodiment, the invention provides a method oftreatment of an ischemic tissue comprising measuring local tissueconditions in a host and modulating oxygen levels of a reperfusate beingdelivered to the host based on the measurement. The measurement oftissue condition is accomplished using a tissue condition monitor. Thetissue condition monitor is linked, directly or indirectly, to areperfusion controller that controls the oxygen content of a perfusategenerated by a reperfusion generator. The controller modulates thereperfusion generator in response to a signal from the tissue conditionmonitor to deliver differing levels of oxygenated fluid to the ischemictissue. In this embodiment the controller may modify oxygen level of thereperfusate based upon a pre-set algorithm or protocol or the operatormay override any pre-set protocol to modify the perfusate manually.

In certain embodiments, the oxygen level of the reperfusate is directlymodulated by changing the oxygen content of the fluid. In otherembodiments, the oxygen levels reaching the tissue are modulated byaltering the flow rate of the fluid, or by altering an rate of mixing ofa supply of oxygenated and deoxygenated fluids. The deoxygenated fluidand/or the oxygenated fluid can be blood. In some embodiments, theoxygen levels are measured as a partial pressure of oxygen in the fluid.The oxygen levels can also be measured as an oxygen saturation or oxygencontent of the perfusate.

In another embodiment of the invention, a measurement of local tissueconditions by the tissue condition monitor, which may be a sensor orprobe, is transmitted to the reperfusion controller, which sets thedesired starting oxygen level of the reperfusate produced by thereperfusate generator. The oxygen level of the reperfusate is adjustedby the controller in response to the condition of the ischemic tissue.The reperfusate is used to reperfuse the ischemic tissue. As theischemic tissue recovers and the local tissue conditions change thereperfusion controller adjusts the desired reperfusate oxygen levels tocontrol the therapy based on continued, ongoing tissue conditionmeasurements. Such perfusate oxygen levels can be set using an algorithmor protocol that can be selected based upon the initial tissue conditionor that may be manually controlled by the operator.

In another embodiment, the invention provides an apparatus for adaptivereperfusion that comprises a tissue condition monitor, a reperfusioncontroller operably connected to the monitor, and a reperfusategenerator that is controlled by the reperfusion controller.

The tissue condition monitor can be one or more probe or sensor in anyform that can be either inserted into the tissue being measured or canbe extraneous to the tissue. The monitor can collect data from multipleprobes or sensors and integrate the data to provide a signal to thereperfusion controller. In one exemplary embodiment, the condition ofthe ischemic tissue is measured using at least one oxygen probe orsensor that has been guided into the heart and inserted into the cardiactissue. The cardiac tissue that the probe or sensor measure hastypically been oxygen deprived for a period of time and is ischemic. Themonitor measures the identified parameter, such as oxygen level of thetissue, and transmits a signal to the reperfusion controller. The deviceand method described herein allow the ability to set a reperfusionstrategy based upon the actual condition of the tissue as reflected bythe tissue condition monitor.

The reperfusion controller commands the reperfusion generator togenerate reperfusate to the specified oxygen content. The controllerprocesses the signals received from the tissue condition monitor toderive a measurement of a parameter, such as local oxygen levels, in theischemic tissue. The controller compares the measured levels to adesired tissue parameter level, and commands the reperfusion generatorto generate reperfusate with an oxygen content, flow rate or mixturerate that causes tissue parameter levels to change in a way to match thedesired tissue parameter profile. Typically, the controller thereforeincludes a microprocessor to compare the levels and provide theappropriate commands.

The reperfusion controller may use tissue condition measurements asinputs to an algorithm. The reperfusion controller may be automaticallyor manually set in response to tissue conditions. In specificembodiments, the reperfusion controller is automatically set and isresponsive to a predetermined algorithm. The reperfusion controlleralgorithm may be a closed loop control algorithm. The algorithm mayimplement a closed loop servo. The algorithm may utilize data parametersthat can be changed by a user or by an external device. The algorithmmay take into account the passage of time.

In certain embodiments, the reperfusion generator may be a venous bloodoxygenation apparatus, such as a heart-lung machine, that can increasethe oxygen levels in a fluid in response to a controller command. Inother embodiments the reperfusion generator may be a deoxygenator thatcan reduce the oxygen content of an input fluid, such as arterial bloodor previously oxygenated blood, to a level commanded by a controller. Inanother embodiment the reperfusion generator may be any device that cangenerate desired oxygen levels in a reperfusate in response tocontroller commands. In one exemplary embodiment of the invention, thereperfusion generator is an apparatus such as that disclosed in U.S.Pat. No. 7,455,812. In this embodiment, a mixed blood line can providethe reperfusate. The mixed blood line provides a mixture of bothoxygenated and deoxygenated blood to the tissue. The mixed blood lineallows for gradually increasing the oxygen tension of the perfusatewithout circulating venous blood through an oxygenator, which may limitthe protective nature of venous blood.

In certain embodiments, the reperfusate is delivered to the ischemictissue through a catheter. In some embodiments of the invention, theinvention is used in a percutaneous procedure. In other embodiments, thereperfusate is delivered by tubing from the reperfusate generator to theischemic tissue zone. The catheter or tubing may be connected to theischemic tissue either percutaneously or through a transthoracicprocedure. In certain embodiments, the reperfusion generator is furtherattached to an interventional catheter. In this embodiment, thereperfusate can be delivered to the ischemic tissue during apercutaneous coronary intervention (PCI) using a catheter that has beenintroduced into a coronary blood vessel. In this embodiment, theinterventional catheter would be configured to provide the perfusate ina manner that would block the flow of unmodified blood to the region.Such a catheter can be configured with a proximal occluding member. Acatheter can be configured to allow flow to only the infarct vessel(that which is being intervened upon). Alternatively, the catheter couldbe configured to be attached to a more global perfusion device, or, inone non-limiting example can be an aortic catheter that contained theproximal occluding member. Such catheters are described, for example, inU.S. Pat. No. 6,866,650 to HeartPort. In one embodiment the proximaloccluding member is threaded through a central or more peripheral lumenof such a catheter. The catheter can be positioned during a percutaneousor transthoracic procedure to avoid exposure of the tissue to aperfusate with an undesirable composition or oxygen level. The tissuecondition monitor can gather and then provide data to the reperfusioncontroller for the desired starting composition of the perfusate as wellas providing ongoing data as recovery and reperfusion progress, thusdetermining the shape of the oxygen curve as a function of time.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic of the apparatus described herein.

FIG. 2 is a schematic of the tissue condition monitor.

FIG. 3 is a schematic of the method of target therapy curve selection.

FIG. 4 is drawing of exemplary target therapy curves.

FIG. 5 is a schematic of the method of controlling the reperfusateoxygen levels.

DETAILED DESCRIPTION

The present invention is based on a recognition that reoxygenation ofpreviously ischemic tissues should be modulated in response to localconditions and based, further, upon an appreciation that such conditionschange dynamically during pharmacological and mechanical alterations ofthe circulatory system. The methods and apparatus described hereinprovide a tool that can respond to the local tissue environment of theischemic heart by measuring both the antecedent and dynamically changingcondition of the tissue affected by the existent ischemia and ongoingreperfusion; then controlling oxygen levels of the reperfusate as afunction of time during re-introduction of oxygen. As recovery begins,it is intended that this apparatus and method allow ongoing adjustmentof perfusate oxygen levels in response to the actual conditions of thatischemic tissue. This is in contrast to existing techniques thatestimate or that simply ignore the tissue condition.

Indeed, under existing guidelines, many patients are misjudged to haveeither more or less severe antecedent ischemia based solely uponclinical parameters defined decades earlier rather than a precisemeasurement of tissue condition. Such a tissue condition monitor can belinked to a perfusate device that is operable and configured to delivera “mixed blood line” perfusate that is modifiable with respect to oxygenlevels as a function of time. In some embodiments, the device togenerate the perfusate is one such as that described in U.S. Pat. No.7,455,812. Such a mixed blood line or other configuration forcontrolling oxygen levels may be connected to an interventional cathetersystem or may be configured to be a part of a systemic cardiopulmonarybypass circuit with a separate cardioplegia or coronary perfusioncircuit.

In many clinical cases treatment is delayed or denied in the acutepresentation because of potential for tissue damage that may occur uponthe reintroduction of oxygen in circumstances in which antecedentischemia is particularly protracted or severe. Treatment may also beinitiated inappropriately based upon clinical parameters thatunderestimate the severity or duration of the antecedent syndrome. Insuch circumstances, extensive reperfusion damage may occur that was notanticipated based upon an erroneous judgment of tissue condition. Thepresent invention is particularly useful in those patients with the mostprotracted or severe pre-existent ischemia because the apparatus canmitigate injury to such tissue upon acute reperfusion. It should bepointed out that the antecedent severity of the tissue ischemia may notbe accurately reflected by the appearance of the patient or anyexternally measurable clinical parameter as these may not be congruous.

The present invention addresses the acute tissue condition, allowing afeedback loop that is configured to provide a real-time guide to theinterventional strategy. The invention allows the clinician to addressall patient groups whether ischemia is protracted and/or severe orabbreviated and/or mild without being misled by the clinical appearanceof the patient on either end of the clinical spectrum.

Accordingly, in one embodiment, the invention provides a method oftreating an ischemic event in a host comprising measuring local tissueconditions in a host tissue and modulating oxygen levels of areperfusate being delivered to the host based on the measurement. Themeasurement of tissue (110) condition is accomplished using a tissuecondition monitor (120). The tissue condition monitor is linked,directly or indirectly, to a reperfusion controller (130) that controlsthe oxygen content of the reperfusate (150) generated by a reperfusiongenerator (140). The controller modulates the reperfusate to deliverdiffering levels of oxygenated fluid to the ischemic tissue.

In certain embodiments, the oxygen level of the reperfusate is directlymodulated by changing the oxygen content of the fluid. In otherembodiments, the oxygen levels reaching the tissue are modulated byaltering the flow rate of the fluid, or by altering a mixture rate ofoxygenated and deoxygenated fluids.

Clinical Scenarios:

The methods and apparatus of the present invention can be useful in avariety of clinical scenarios.

Acute percutaneous coronary intervention (acute PCI) with or withoutintra-aortic balloon or cardiopulmonary support during evolving ischemiacan be facilitated by the method and apparatus described herein. Anassessment of the ischemic conditions with the tissue condition monitorallows an appropriate starting point for initial reperfusate oxygenlevel. In certain instances, the patient is administered apharmaceutical agent, for example, vasoactive or beta-blockingpharmaceutical agents. Intra-aortic balloon support is widelyappreciated to support the coronary and systemic circulations byenhancing perfusion in both and, as such, affecting the supply side ofthe ischemia balance and by enhancing tissue oxygen delivery (systemicor coronary). This explains why such support is often used in patientswith cardiogenic shock prior to, or in lieu of, other forms ofmechanical circulatory support (such as cardiopulmonary bypass, ECMO orventricular assist or artificial heart pump support). Such support witha balloon pump could alter the starting point of perfusate oxygen level.

The present invention can also be useful in coronary bypass grafting,either on- or off-pump and with or without balloon support. In emergencycoronary bypass operations, whether done “on pump” or “off pump”, littleappreciation exists for any assessment of the antecedent condition ofthe tissue or the manner in which the condition of the tissue may bealtered by intra-aortic balloon support, the initiation ofcardiopulmonary bypass or even the induction of general anesthesia. Thepresent invention allows for a very precise, surgical accounting oftissue condition and could be expected to enhance the practice byallowing for a manipulation of perfusate oxygen tension, saturation orcontent in response to real-time tissue conditions. The altered oxygencontent fluid can be delivered to the tissue during or via vein graftbypass or catheter based perfusion to the infarct (or other) artery.Vein graft perfusion after completion of a coronary anastomosis can befacilitated by a blood pump as described in the present invention. Sucha perfusion pump can be free-standing in “off-pump” cases or integratedinto a heart-lung machine in “on-pump” cases as described in U.S. Pat.No. 7,455,812 and configured to receive a mixed blood supply thatcarefully controls oxygen partial pressure, saturation or content. Incertain embodiments, the intervention is thus a vein graft interventioncan be facilitated by the present invention after careful assessment ofthe condition of the tissue is presented to the operator in theoperating room. In addition, appropriate reperfusion control may beuseful in non-cardiac ischemia, such as during limb reperfusion or braininjuries including stroke and traumatic brain injury (TBI).

Tissue Condition Monitor

It is well established that patients can adapt to levels of chronic orintermittent coronary ischemia to differing degrees. Even varyingintensity of acute ischemia can be remarkably well tolerated,particularly if they are not protracted events. Different patients whopossess identical coronary disease anatomy (including total occlusions)may have adapted to this anatomy as it progressed over a chronictime-frame. In another example, coronary anatomy in the same patientthat does not necessarily change may take on different significance inthe setting of an acute coronary syndrome. As such, the anatomy of theepicardial vessels tells only one part of the story. The overallclinical condition of the patient tells another. For that reason,“gross” or “macro” measurements (i.e. angiographic appearance) may guidethe clinician or provide a road map of where to inflate a balloon orwhere to place a stent, however they do not acurately reflect thecondition of the tissue supplied by that artery at any given time.

In the setting of the treatment of acute evolving coronary ischemia, thepresent invention allows the operator to respond to actual tissueconditions rather than the patient's clinical appearance, which may beinaccurate. The best previously available clinical constructs for theguidance of interventional treatment are based upon data frominterventional studies of another era and the entire premise upon whichthese guidelines are based allows no assessment of the tissue condition.While timely reperfusion or opening of the “culprit” vessel has beenshown to be useful in saving lives and improving outcomes, damage to theheart during reperfusion therapy adds to the injury.

Therapeutic, acute percutaneous balloon catheter intervention with orwithout stenting with advanced anti-platelet and other anticoagulationor urgent coronary bypass surgery are still the only known and besttherapies available to establish reperfusion of the ischemic heart. Itis clear that the timing of such intervention has been based uponinexact criteria as acute mortality rates remain high in subsets ofpatients (e.g. cardiogenic shock) and therapy is not offered to themajority of patients during the acute event because of the fear of poorclinical outcomes that can accompany reperfusion or other additionalcardiac injury during the re-establishment of flow into the ischemictissue.

Although the clinical appearance of a given patient and the responses toreduced oxygen availability in acute or chronic situations vary greatlyfrom patient to patient (based upon reserve, adaptation, chronicity ofatheromatous growth and development of collateral flow), cells subjectedto protracted and uncompensated ischemia react in a remarkably similarand in a highly evolved manner to attempt to adapt to ischemicconditions. The cellular changes that proceed during these eventsultimately lead to disturbances from which the cell may or may notrecover. The cellular recovery depends largely upon what happens duringthe phase in which oxygen and other nutrients are reintroduced Duringthe reestablishment of blood flow and reintroduction of molecularoxygen, the relationship between the availability of oxygen to thetissue, the demand for oxygen in the tissue and the precise manner inwhich oxygen is reintroduced and the pre-existing cellular conditionsall govern whether recovery or further tissue injury occurs. Inaccordance with this discussion of tissue condition monitors, it is,therefore, important to have a tool to determine the presence, absenceand severity of the cellular ischemic conditions at the time reperfusiontherapy is undertaken.

The purpose of the tissue sensor in ongoing acute coronary ischemia isto accurately determine the severity of the cellular alterationspresent. By measuring tissue conditions during therapy rather thanlooking at the outward appearance of the patient and the EKG as a“clinical” presentation, life saving and “tissue-saving” therapy can beoffered to a broader range of affected patients. For illustrativeexample; while it is widely accepted that the clinical presentation ofcardiogenic shock requires more than 40% of functioning myocardium to bepoorly contractile (hypokinetic or akinetic), not all of that tissue isnecessarily acutely ischemic nor irreversibly damaged. While it iswidely accepted that such a patient undergo immediate percutaneous orsurgical reperfusion therapy, the present invention allows for anaccurate assessment of the affected tissue at the cellular level. Thiscan allow the careful tailoring of therapy to each individual patientand each of the affected myocardial areas to guide oxygen partialpressure and the timing curve of therapy as compared to the“one-size-fits-all” approach of previous decades.

In certain clinical instances, the demand of the heart tissue for oxygenmay be reduced. For example, in cases in which mechanical support isused to unload the heart (either with a balloon pump or cardiopulmonarybypass) the reduction in demand for available oxygen must be accountedfor in the resuscitation phase of treatment. When the heart is doing nopressure-volume work, the demand of the heart tissue for oxygen andnutrients is recognized to be about 50% below basal conditions. Ininstances in which the heart is stopped using cardioplegia, the demandis lowered to about one tenth normal. In contrast, in an awake patientwithout mechanical support the heart may be working at much higher thanbasal conditions exacerbating both global and regional ischemicconditions and setting the stage at the cellular level for increasingthe likelihood that serious reperfusion damage will result upon eitherreintroduction of molecular oxygen by reestablishing flow or by theelimination of ischemic conditions. It should be pointed out for thepurpose of clarity and relevance to the present invention that these twoscenarios may be effected in various ways and by alterations in bothsupply of and demand for oxygen.

The tissue condition monitor can comprise a sensor embedded in themyocardium to give tissue specific information. However, the monitor mayalso lie within the extensive system of coronary venous drainage givinginformation regarding regional oxygen extraction. In certainembodiments, the monitor is not a sensor, but is a molecular biomarker(probe) that is infused and taken up by the machinery of the cells toprovide a particular readout that can be measured by external sensorssuch as visual, electromagnetic or nuclear imaging. The tissue conditionmonitor may also be a non-invasive modality such as MRI, PET orultrasound.

The tissue condition monitor can comprise one or more sensors in anyform that can be either inserted into the tissue being measured or canbe extraneous to the tissue. The tissue condition sensor can comprise asignal processing means to process the raw signals being generated by atissue sensor or sensors. The tissue condition sensor may be guided tothe tissue of interest with the aid of an imaging means. Such imagingmodalities include ultrasound, fluoroscopy, PET and MRI.

In one embodiment, a simple echocardiographic assessment of a wallmotion abnormality and regional EKG changes would allow the positioningof a tissue sensor using fluoroscopy in a “culprit” coronary artery, inthe area of venous effluent drainage of that region or in the sameregion that appears ischemic based upon the assessed changes seen bymyocardial contrast echocardiography. Other techniques using informationon the tissue that is affected to position the sensors include positrontomography (PET) scans or cardiac magnetic resonance (MM). Nuclearmedicine scanning for the uptake of thallium or other like molecules candefine clinical ischemia as well.

Typically, the more intense and protracted the ischemia; the higher thelikelihood that the tissue is overwhelmed by oxidative stress andreactive oxygen intermediates are formed rather than channelingmolecular oxygen into oxidative phosphorylation and cellular recovery.These oxygen free-radicals can cause lipid bilayer peroxidation and theinitiation of violent calcium oscillations that lead to contracture andstunned myocardium at one end of the spectrum to calcium overload andcell death at the other. Further, such oxidative stress in thosecircumstances has been linked to the upregulated activity ofinflammatory mediators, the expression of cytokines, adhesion moleculesand, possibly, the expression of transplant rejection-related, majorhistocompatibility complex (MHC) antigens.

Embedded tissue sensors may measure, as non-limiting examples, tissuepH, PO₂, pCO₂, temperature, ion concentrations including potassium,sodium or calcium concentrations in the extracellular environment,cellular membrane depolarization, hyperpolarization or resting membranepotential, cyclin dependent kinases (CDK), B-type natriuretic peptide(BNP), tumor necrosis factor α (TNF-α), creatine phosphokinase, lipidperoxidation byproducts such as aliphatic aldehydes including malonicdialdehyde, PMN elastase, NFkB, Na—H Exchange pump activity. U.S. Pat.Nos. 5,813,403, 6,564,088, and 6,766,188, describe a method and devicefor measuring tissue pH via near infrared spectroscopy (NIRS). NIRStechnology allows the simultaneous measurement of tissue saturation ofoxygen, carbon dioxide as well as pH.

The monitor can collect data from multiple sensors and integrate thedata to provide an integrated signal or signals to the reperfusioncontroller. In one exemplary embodiment, the condition of the ischemictissue is measured using at least one oxygen sensor that has been guidedinto the left ventricle of the heart and inserted into cardiac tissue. Anon-limiting example of such a monitor would be one that is advancedinto the LV chamber on a catheter-based carrier and then deployed underguidance of a trans-esophageal echo probe to engage the tissue to acertain depth; usually as deep as or deeper than the sub-endocardiallayers. The cardiac tissue that the sensor is inserted into hastypically been oxygen deprived for a period of time and is ischemic. Themonitor measures the identified parameter, such as oxygen level of thetissue, and transmits a signal to the reperfusion controller. Anotherillustrative example of tissue examination under such conditions is theuse of myocardial contrast echocardiography, which could also be appliedto determine acutely affected tissue to allow guidance of a sensor intoposition for a more accurate probing of tissue condition. Othertechniques to locate sensors include positron tomography (PET) scans orcardiac magnetic resonance (MRI). These illustrative examples areintended to be non-limiting.

In one embodiment shown in FIG. 2 (200), a tissue sensor (240) isinserted in the ischemic cardiac tissue (250) and is used to sense atissue parameter, such as pO₂. The raw signal from the tissue sensor isprocessed by the signal conditioning circuit (230) to generate a valuerepresentative of the parameter being measured. This value is processedby the interface (220) that takes the output of the signal conditioning(230) block and configures it in a signal (210) appropriate fortransmission to the reperfusion controller.

The condition of the ischemic tissue may also be measured by anon-invasive means. This measurement may measure parameters relating tothe local chemistry or physiology of the tissue or may measuremorphologic parameters. Current echocardiographic and EKG changes canallow determination of wall motion abnormality and a region that appearsischemic based upon the changes seen on a 12-lead EKG. Nuclear medicinescanning for the uptake of thallium or PET or SPECT imaging usingradiolabeled RBC's can all define cellular metabolism or degree ofperfusion as well. The tissue condition measurement may reflectfunctional parameters such as motion, contractility or cellularrespiration.

In some embodiments the measurement of the tissue condition is madeusing at least one tissue sensor. The tissue sensor may measure pO2 inthe tissue or may measure oxygen saturation of hemoglobin within redblood cells in circulating blood in some blood vessel that can provideinformation on oxygen extraction or cellular metabolism. The tissuesensor may also measure any other parameter that can be linkedclinically and/or experimentally to severity of ischemia that may beused by the reperfusion controller to determine appropriate perfusateoxygen tension or composition. The tissue condition monitor may alsomeasure more than one parameter. In embodiments where more than oneparameter is measured, a single tissue sensor may be used to make themeasurement or a plurality of sensors may be employed. In someembodiments the condition of the ischemic tissue is sensed by a sensorpositioned in the ischemic tissue itself. In other embodiments thecondition of the ischemic tissue is sensed by a sensor remote from theischemic tissue itself In some other embodiments; a plurality of sensorsmay be deployed under some guidance to the operator and positioned inboth ischemic and non-ischemic areas of the heart. One non-limitingexample of such a preferred embodiment would be that the processor wouldrapidly compare the tissue parameter of the ischemic to the non-ischemicarea and set the controller to perfuse the tissue in a pre-set manner.Such preset manner could be over-ridden manually if the operatorchooses.

In some embodiments the tissue condition monitor includes a sensorguided to the ischemic area using visual guidance from a fluoroscope,myocardial contrast echocardiograph, and ultrasound imaging system, MMscanner, PET scanner or other imaging modality. This imaging modalitymay be used to detect areas of compromised cardiac function (e.g.abnormal heart wall motion) indicating ischemic tissue. The imagingmodality may also be used to help guide the tissue sensor itself forpositioning.

In yet another embodiment, the tissue condition monitor is positioned byadministering a molecular probe to the host wherein the molecular probeis taken up by uninjured cells and is configured to be detectable as aguide to position the tissue condition monitor.

Sensors that can assess markers of acute ischemia, the consequences ofreperfusion injury or other processes that occur during acute coronaryevents may be used in the tissue condition monitor. In certainembodiments, the condition of the ischemic tissue may be inferred frommeasurements made not in the tissue itself. In one embodiment, aparameter or parameters of blood distal to the ischemic tissue is/aremeasured. In the event that the blood distal to the ischemic tissue ismixed with blood from other areas, the reperfusion controller may makecalculations to infer the contribution to the measured parameter of theblood from the area of interest. The blood measured may be in thecoronary sinus, measured with a fluid sensor, a sensor with oxymetriccapability or some other means by which to determine oxygen extractionas a surrogate for ischemic conditions. It may be determined that thebest scenario to determine the output of the controller is to measure acombination of such parameters and then to evaluate a ratio or someother relationship of one parameter to the other to determinereperfusion controller output.

The sensor may be attached to a support structure such as a stent,guidewire, or catheter. In a further embodiment, a catheter is disclosedthat extracts samples to a sensor outside the body for monitoring asubstance or property of the patient sample.

In certain embodiments, the sensors specifically assess the saturationof oxygen or the pO₂ in coronary sinus effluent. Further, intra-coronarysinus pH changes may be highly related to the severity of the ischemicconditions. In addition, factors indicative of tissue condition that maybe monitored in the coronary sinus include leukocyte elastase, tumornecrosis factor (TNF), basic FGF, von Willbrand factor (as a surrogatefor P-selectin), p-selectin, nitrate and markers that may representbi-products of lipid peroxidation (like malondialdhyde) or othercytokines. This list is intended to be illustrative rather thanlimiting. Such coronary sinus sensors or probes that now exist or thatmight be invented in the future can be used to assess the progress,safety and subsequent composition of the ongoing reperfusion therapy.

In certain embodiments, tissue CO₂ can also be measured, for example asdescribed in U.S. Pat. No. 6,055,447, which describes a tissue CO₂sensor. Sensors can be of any type, but include fiber optic sensors,nanoparticle sensors, and even biologic sensors. US Patent PublicationNo. 20060079740 to Silver, et al. provides a sensor for implantationwithin a blood vessel that can detect nitric oxide or a nitric oxidemetabolite, substances such as glutamate, aspartate, arginine,citrulline, acetylcholine, calcium, potassium, or dopamine.

Reperfusion Controller

The reperfusion controller commands the reperfusion generator togenerate reperfusate to a specified oxygen content. The controllerprocesses the signals received from the tissue condition monitor toderive a measurement of a parameter, such as local oxygen levels, in theischemic tissue. The controller compares the measured levels to adesired tissue parameter level, and commands the reperfusion generatorto generate reperfusate with an oxygen content, flow rate or mixturerate that causes tissue parameter levels to change in a way to match thedesired tissue parameter profile. Typically, the controller thereforeincludes a microprocessor or other logic to compare the levels andprovide the appropriate commands.

In some embodiments, the reperfusion controller receives sensor inputthat has already been processed to provide a final sensor reading. Inother embodiments, the reperfusion controller processes raw sensorsignals to derive a sensor reading. The reperfusion controller may takeone or more sensor signals as inputs. The controller may take inputsfrom modalities that generate information relating to the condition ofthe ischemic tissue. The reperfusion controller may also take input froma user or from an external device. This input may be information relatedto the condition of the patient. This input may also be treatmentdirection from a user. In certain embodiments, the reperfusioncontroller automatically controls the reperfusate oxygen level based ona preset algorithm. In other embodiments, the reperfusion controllercontrols the reperfusate oxygen level based on a manual input from anoperator.

Control

The present invention addresses the actual condition of the affectedtissue and microcirculation. The essence of the invention relates tousing real-time feedback to identify the underlying condition of thetissue which relates to its potential response to therapy, rather thanestimating tissue conditions based upon clinical appearance, EKGchanges, elevated serum biomarkers or other factors that are eitherglobal or delayed. The therapy described herein addresses the conditionof the underlying tissue to provide a real-time feedback that isdeployable in the ER, the ICU or the cath lab that guides reperfusiontherapy. The technology takes into account factors affecting oxygensupply (i.e. the narrowed/occluded arteries, blood hemoglobin levels,evidence of endothelial activation, etc.) and demand (i.e. how hard theheart is working, ventricular wall stress, afterload, preload, heartrate, etc.). To date, very little control over anything other than thetiming of intervention has been used and accurate or reliableresuscitation of threatened tissue has not been possible. Even lessinformation regarding the success or failure of reperfusion in real timeat the cellular, microcirculatory or molecular levels has beenavailable.

The condition monitored can be of individual cells or a reflection ofthe condition of the micro-vascular environment (including endothelialactivation, platelet adherence or release into the microcirculation ofmarkers of injury) and provide a real time reflection of metabolicprocesses, microcirculatory failure or cellular injury and could becorrelated with the appropriate perfusate pO₂.

The reperfusion controller may use tissue condition measurements asinputs to an algorithm. The controller may also use inputs not relatedto the condition of the ischemic tissue as inputs to an algorithm. Suchinputs may be information regarding the patient, time since thebeginning of the event, parameters that were measured beforeintervention such as muscle wall abnormalities, or other informationthat can be inputs to an algorithm. Such inputs may include input from auser. The output of the reperfusion controller may control informationfor a reperfusate generator.

The reperfusion controller algorithm may be a closed loop controlalgorithm. The algorithm may implement a closed loop servo. Thealgorithm may utilize data parameters that can be changed by a user orby an external device. The algorithm may take into account the passageof time.

The algorithm for the reperfusion controller may be fixed or may bechanged from time to time. In the case where it is changed, it may bechanged to another algorithm previously stored in the controller or itmay be downloaded from a source external to the controller. Thealgorithm may be changed by changing the steps it executes or bychanging how the steps are executed.

In one embodiment initial user-input parameters are used to guide thereperfusion therapy. Such parameters may include patient-specificinformation such as age, sex, and time since ischemic event. Thisinformation is input (310) to the reperfusion controller algorithm (300)along with information from the tissue condition monitor (320). In oneembodiment, this information is used to select a target therapy curve(340) from a table (330) of possible curves. The target therapy curvedefines the time-variable target for the tissue condition monitor signalthat the reperfusion control should attempt to achieve. The targettherapy curve may include associated information such as how changes inreperfusate oxygen will affect the measured parameter (negative orpositive correlation) and information as to expected sensitivity of themeasured parameters to reperfusate changes and allowed reperfusatechange slew rates along with total length of therapy. For example, atarget therapy curve for pO₂ would include information that an increaseis reperfusate oxygen content would be expected to increase measuredtissue pO₂ or some other parameter indicating both recovery of cellularand mitochondrial function (including restoration of oxidativephosphorylation and recovery of trans-membrane polarization towardnormal) and the avoidance of producing indicators of, for example, lipidperoxidation.

FIG. 4 shows non-limiting representative examples of three targettherapy curves. In one embodiment the target therapy curve is based onmeasurement of pO₂ (410). In another embodiment the curve is based onmeasurement of pH (420). In a third embodiment, the curve is based onmeasurement of elastase α₁-protease inhibitor complexes (EIC) (430). Inyet another embodiment, the curve is based on measurement of tumornecrosis factor (TNF). In yet another embodiment, the curve is based onmeasurement of basic FGF. In yet another embodiment, the curve is basedon measurement of von Willebrand factor or p-selectin. In yet anotherembodiment, the curve is based on measurement of nitrate. In yet anotherembodiment, the curve is based on measurement of malondialdhyde. Inother embodiments, this curve may actually be a multidimensional“surface” based on the measurement of a plurality of tissue parameters.

The reperfusion controller (130) controls the reperfusion generator(140) in an attempt to cause the measured tissue parameter to track theselected target therapy curve over time. In one embodiment, an algorithm(500) is used to generate the signal to the reperfusion generator. Atthe beginning of the therapy time t is set to zero (510). The startingreperfusate pO₂ (r_pO2) is retrieved from a table associated with thepreviously selected target therapy curve (520). Then the reperfusategenerator is commanded to produce reperfusate having properties r_pO2(530). A time interval delta-t is allowed to pass (540) and then ameasured tissue parameter TPmeas is retrieved from the tissue conditionmonitor (550). TPmeas is compared to the desired parameter level asspecified in the selected target therapy curve for that time TPcurve(t)(560). If the measured parameter is the same as the desired level, theloop continues without changing r_pO2. If there is a difference, adelta_r_pO2 is computed and added to the current r_pO2 to generate a newr_pO2 (570) and loop continues with step 530 with a new pO2 command tothe reperfusate generator. Delta_r_pO2 may be computed by techniquesused in closed loop control algorithms. In one embodiment an equationsuch as delta_r_pO2=(TPcurve(t)−TPmeas)*(sensitivity) could used. Incertain cases, the “sensitivity” can be a negative number, i.e. thecorrelation coefficient is negative.

In certain embodiments, the reperfusion parameters are designed toprovide normalization of perfusion to tissue within one hour ofinitiation. In other embodiments, they are designed to providenormalization in less than one hour, such as in 45, 30 or less than 30minutes such as, for example, 25, 20, 15, 10 or 5 minutes afterinitiation of therapy. In some embodiments, additional measurements areconducted on tissue conditions after therapy to identify potentialinjuries.

Reperfusion Generator

In certain embodiments, the reperfusion generator may be a venous bloodoxygenation apparatus that can exploit the protective nature of venousblood perfusion during acute reperfusion of ischemic tissue, such as aheart-lung machine, and that can increase the oxygen levels in a fluidin response to a controller command. In such an embodiment it isrecognized that the protective nature of venous blood may relate to thelower oxygen tension present or may relate to a different component ofvenous blood. In other embodiments the reperfusion generator may adeoxygenator that can reduce the oxygen content of an input fluid, suchas arterial blood or previously oxygenated blood, to a level commandedby a controller. In another embodiment the reperfusion generator may beany device that can generate desired oxygen levels in a reperfusate inresponse to controller commands. The reperfusion generator can also beany device that can modify the oxygen level delivered to the tissue,i.e. by modifying the flow rate, in response to controller commands.

In one exemplary embodiment of the invention, the reperfusion generatoris an apparatus such as that disclosed in U.S. Pat. No. 7,455,812. Inthis embodiment, the mixed blood line can provide the reperfusate. Themixed blood line provides a mixture of both oxygenated and deoxygenatedblood to the tissue and exploits the protective nature of venous bloodfor as long as the clinical situation warrants that is based upon theprecise condition of the tissue.

In certain embodiments, the reperfusate at a point in the processincludes a high level of oxygen, such as through an oxygensupersaturated fluid. However, the high level of oxygen is typically notdelivered until after the tissue condition monitor provides measurementsthat indicate that the tissue has recovered sufficiently to reduce riskof reperfusion/reoxygenation injury. This recovery might be signaled ina number of ways or be reflected by the tissue condition monitor sensoror probe, but, as a non-limiting example, may be signaled by anormalization of pH.

In certain instances, the reperfusate undergoes further processing suchas by inserting leukocyte filters into the delivery circuit and bygradually adjusting the admixture of venous and arterial blood in acarefully controlled reoxygenation strategy.

In some embodiments, the reperfusion generator regulates the rate atwhich blood is delivered to the tissue. For example, the reperfusiongenerator can regulate the inflation of a balloon in the vessel. Inother embodiments blood may be supplied in a compartmentalized fashionby engaging a proximal occluding member in both the artery upon whichthe intervention is being performed and the other arteries. As describedpreviously, the tissue within the myocardium may be affected by ischemiaalong a spectrum of severity and in areas other than that supplied bythe “infarct” artery. As such, it is desirable to be able to control, ina compartmentalized way, the perfusate to both the acute “infarctartery” and the other arteries that may supply tissue that is affectedby reduced collateral flow. In one embodiment, the catheter may be acentral aortic catheter that has a large occluding member but thatallows for the positioning of more than one separate catheter that eachperfuses a different artery differently. In certain of theseembodiments, the central lumen of the central aortic catheter can alsobe used to compartmentalize perfusion for global coronary perfusionwhile, simultaneously, a second and a third catheter inserted viaanother lumen (central or peripherally located) can be theinterventional stent deploying catheter and a separate catheter withanother downstream occluding member to control individual arteryperfusion. In such an embodiment the elaborate catheter system describedwould be connected to the reperfusion generator described and, likely, asecond perfusion device that was also adjustable with regard to oxygenpartial pressure and various other parameters.

The reperfusate may be blood, a non-blood fluid or a mixture of the two.In certain embodiments, the reperfusion generator provides distinctreperfusates to the cardiac tissue and to non-cardiac tissue such as thebrain. The reperfusates can include one that addresses the cardiactissue appropriately and that perfuses specific coronary arteries (ormultiple arteries) during PCI or surgery and is controlled by thecontroller, and another that allows for adequate oxygen delivery to thebrain separate from the controller. Unless systemic oxygen tension isextremely low, as in cyanotic conditions or in cases where there issignificant concomitant pulmonary disease or shock, separate perfusatesallow the coronary perfusates to “match” the usually far lower pO₂ ofthe ischemic cardiac tissue based upon a real-time assessments.

Delivery

In certain embodiments, the reperfusate is delivered to the ischemictissue through a catheter. In other embodiments, the reperfusate isdelivered by tubing from the reperfusate generator to the ischemictissue zone. The catheter or tubing may be connected to the ischemictissue either percutaneously or through a trans-thoracic procedure or,in other embodiments, through both catheters, perfusion lines that areattached to the generator or via bypass grafts that are constructed viaa trans-thoracic procedure. In certain embodiments, the reperfusiongenerator is further attached to an interventional catheter or may beconnected simultaneously via several catheters in combination withanother perfusion device (such a heart-lung machine).

In one embodiment, the reperfusate can be delivered to the ischemictissue during a percutaneous coronary intervention (PCI) using acatheter that has been introduced into a coronary blood vessel. Incertain embodiments, the reperfusion generator is attached to a veingraft or other surgically constructed conduit that has been surgicallyconnected to the tissue via an anastomosis one or more blocked arteries.In certain other embodiments a combination of vein grafts perfused via abranched perfusion device can be connected to the reperfusion generatoror a separate perfusion device (such as a heart-lung machine) whilesimultaneously a PCI catheter may also be providing controlledreperfusate to the “infarct” artery.

In some embodiments of the invention, the invention is used in apercutaneous procedure. In other embodiments, the invention is usedduring a transthoracic procedure. In particular embodiments of theinvention, the host or subject to which the method and system is appliedis a human who might be undergoing a “hybrid” percutaneous andtrans-thoracic procedure. In specific embodiments, the host is a humanwho is in need of prevention of reoxygenation injury. In certainembodiments, the subject is a human patient with cardiovascular disease.In certain other embodiments, the subject is a human patient undergoinga transthoracic procedure. The procedure and apparatus can be used in asubject undergoing surgery after a cerebral infarct and concomitantischemia, for example after a stroke. In addition, the patient can beundergoing intervention for an ischemic event in a limb. In cases inwhich the ischemic tissue is not cardiac tissue, the tissue sensors areplaced in and measure the ischemic tissue, whether that is cardiac ornot.

The methods and apparatus of the invention can be useful in the clinicalarena of either cardiac surgery or interventional cardiology. They canbe applied in acute percutaneous coronary intervention or urgent bypasssurgery, but as discussed above, are also applicable in evolving“hybrid” treatments which may combine both PCI and surgicalinterventions. In some embodiments, it is intended to provide treatmentfor acute myocardial infarction with ST segment elevation. In certainembodiments, it is useful in treatment of “acute coronary syndrome”(ACS), which includes unstable angina and non-ST segment elevationmyocardial infarction in which different areas of the heart mayexperience serious but variable degrees of ischemia along a spectrum ofseverity, which can be assessed properly by the tissue conditionmonitors to construct or prescribe an appropriate reperfusion strategy.Typically, ACS occurs when an unstable plaque (potentially due to plaquerupture) leads to an acute and localized thrombosis in an area ofstenosis or narrowing of a blood vessel, leading to ischemic regions inthe tissue but which may also cause a reduction in collateral flow thathas developed over time to other regions that results in ischemia thatis not readily apparent.

The resultant infarction (the totality of tissue injury) occurs by avariety of mechanisms that relate to both the initial event and themanner in which flow is reestablished and oxygen is reintroduced. Theinitial ischemic insult sets the stage for cell death because of aprotracted lack of oxygen that renders the cells unrecoverableas well asbecause of additional injury that occurs upon reoxygenation. This typeof injury (reperfusion/reoxygenation) may relate to oxygen radicalinjury, microvascular failure and so-called “no-reflow”, enhancedinflammation and leukocyte adherence (which goes hand-in-hand withoxygen radical formation), cardiomyocyte contracture via calciumoverload and paralysis, platelet thrombin aggregation upon activatedendothelial cells, among other mechanisms.

It will be apparent to one of skill in the art that the embodimentsprovided are merely exemplary, and that the invention should not be solimited. Accordingly, those of skill in the art will recognize variousalternative designs and embodiments for practicing the invention. Thoseof skill in the art will also recognize its potential for use in bothclinical and animal research to define alternatives and the mostappropriate reperfusion curves that may vary as a function of time indiffering situations.

1. An apparatus for adaptive reperfusion that comprises: a tissuecondition monitor wherein the tissue condition monitor measures ameasured tissue parameter associated with an ischemic tissue within ahuman body, a reperfusion controller operably connected to the tissuecondition monitor and receiving input from the tissue condition monitoras to the measured tissue parameter of the ischemic tissue, and areperfusate generator that is controlled by the reperfusion controllerto create a reperfusate, wherein the reperfusion controller includes atleast one target therapy curve from which a target therapy curve can beselected and the at least one target therapy curve has at least onetissue reperfusion parameter that changes over time, and wherein thetissue condition monitor provides feedback to the reperfusion controlleras to the measured tissue parameter to control the reperfusion generatorto cause the measured tissue parameter associated with the at least onetissue reperfusion parameter to adjust the reperfusate so that themeasured tissue parameter attempts to track the selected therapy curveas to the at least one tissue reperfusion parameter where the differencebetween the measured tissue parameter and selected therapy curve is usedto determine a property of the reperfusate generated by the reperfusategenerator.
 2. The apparatus of claim 1 wherein the tissue conditionmonitor is one or more sensor or probe that can be either inserted intoor taken up by the tissue being measured or can be extraneous to thetissue.
 3. The apparatus of claim 1 wherein the tissue condition monitorcan collect data from multiple sensors or probes and integrate the datato provide an integrated signal to the reperfusion controller.
 4. Theapparatus of claim 1 wherein the tissue condition monitor is a tissueoxygen sensor.
 5. The apparatus of claim 1 wherein the tissue conditionmonitor is a molecular probe that is taken up by the injured cells andis configured to undergo a conformational or other type of change thatis detectable.
 6. The apparatus of claim 1 wherein the reperfusioncontroller is operable to command the reperfusion generator to generatereperfusate to specified oxygen content.
 7. The apparatus of claim 6wherein the reperfusion controller is operable to process signalsreceived from the tissue condition monitor to derive a measurement of aparameter in the ischemic tissue.
 8. The apparatus of claim 1 whereinthe reperfusion controller is operable to compare signals from thetissue condition monitor to a desired tissue parameter level, andoperable to command the reperfusion generator to generate reperfusatewith a specified oxygen content, flow rate or mixture rate.
 9. Theapparatus of claim 1 wherein the ischemic tissue being monitored isselected from the group consisting of organs and muscle.
 10. Theapparatus of claim 1 wherein the reperfusion parameter is at least oneof pO2, pH, and Leukocyte Elastase.
 11. The apparatus of claim 1 whereinthe target therapy curve requires the reperfusate to be delivered at aconstant flow rate.